tbuckley/cabot-search huggingface dataset:
ARC-7: Randomized phase 2 study of domvanalimab + zimberelimab ± etrumadenant versus zimberelimab in first-line, metastatic, PD-L1-high non-small cell lung cancer (NSCLC).
Authors: Melissa Lynne Johnson, William Fox, Yun-Gyoo Lee, Ki Hyeong Lee, Hee Kyung Ahn, Young-Chul Kim, Kang-Yun Lee, Jong-Seok Lee, Xian He, Christine Park, Debbie Pomponio, Thao Dang, Patrick Hoang Phuong, Dimitry S. A. Nuyten, Aparna Madhukeshwar Hegde, Rohit Joshi
Journal: Journal of Clinical Oncology (2022)

397600 Background: While PD-1 inhibitors demonstrated survival benefit compared to chemotherapy in patients (pts) with PD-L1-high, NSCLC, less than half of pts respond to monotherapy. Novel therapeutics or combinations are necessary to improve outcomes. Domvanalimab (D) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domain (TIGIT), thereby reducing immunosuppression of T/NK cells and promoting antitumor activity. Etrumadenant (E) is a selective dual antagonist of both A 2a and A 2b receptors (R) expressed on immune cells thereby reducing immunosuppressive extracellular adenosine. ARC-7 evaluates whether inhibition of TIGIT and adenosine pathways augments activity of zimberelimab (Z) (anti-PD-1 mAb) in pts with PD-L1-high NSCLC. Methods: ARC-7 (NCT04262856) is a randomized, open-label phase 2 clinical trial which enrolled treatment-naïve pts with Stage IV, squamous or non-squamous NSCLC with locally assessed high PD-L1 expression (TPS ≥ 50%), no EGFR or ALK alterations, and ECOG PS ≤1. Pts were randomized (1:1:1) to: Arm 1 (Z): Z 360 mg intravenously (IV) every 3 weeks (Q3W); Arm 2 (DZ): D 15 mg/kg IV Q3W + Z; Arm 3 (EDZ): E 150 mg orally once daily + DZ. Pts in Arm 1 with confirmed progression had the option to cross over to EDZ. Co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS) per RECIST v1.1. Results: As of 31 August 2022, 149 pts received at least one dose of study treatment. Efficacy for this interim analysis included 133 pts randomized at least 13 weeks prior to data cut-off (ITT-13), allowing for ≥ 2 post-baseline scans. With median follow-up of 11.8 months (mo), D-containing arms, demonstrated improved ORR and PFS compared to Z. In the safety population, grade ≥3 treatment-emergent adverse events occurred in 58% (Z), 47% (DZ), and 52% (EDZ). All cases of rash were grade 1-2, manageable with topical corticosteroids, and more common in EDZ (Table). Conclusions: In the first published, randomized dataset evaluating an Fc-silent TIGIT mAb, both D containing arms demonstrated clinically meaningful improvement in ORR and PFS compared to Z. Treatment with Z, DZ and EDZ was well tolerated, and the safety profiles of D-containing arms were similar to Z. Ongoing phase 3 trials are evaluating DZ compared to standard of care in metastatic NSCLC. Clinical trial information: NCT04262856. [Table: see text]
Abstract P2010: Cardiomyocyte Knockout Of Sorbs2 Rewires Cytoskeleton And Causes Dilated Cardiomyopathy
Authors: Jared M McLendon, xiaoming zhang, Daniel Matasic, Mohit Kumar, Olha Koval, Isabella M Grumbach, Sakthivel Sadayappan, Barry London, Ryan L Boudreau
Journal: Circulation Research (2022)

Sorbs2 is a cardiomyocyte-enriched, cytoskeletal adaptor protein and there is growing interest in understanding its roles in cardiac biology and disease. While Sorbs2 global knockout mice display lethal cardiomyopathy with severe arrhythmias, the underlying mechanisms remain unclear, and if this results from intrinsic loss of Sorbs2 in cardiomyocytes (CM) is unknown, as Sorbs2 is also well-expressed in the nervous system and vasculature. Thus, the potential relevance of Sorbs2 in human cardiomyopathy is underexplored. We aim to characterize the effects and potential mechanisms of CM-specific deletion of Sorbs2 on cardiac structure and function in mice, and to further examine Sorbs2 dysregulation in failing hearts and explore potential links between Sorbs2 genetic variations and human cardiovascular disease phenotypes. We report that heart Sorbs2 expression is consistently upregulated in humans with ischemic and idiopathic cardiomyopathies, and in animal models of heart failure (HF). We generated mice with CM-specific loss of Sorbs2 (Sorbs2-cKO) and found early atrial and ventricular conduction anomalies, despite unaltered expression of primary action potential ion channels and gap junction proteins. At mid-life, Sorbs2-cKO mice exhibit impaired cardiac contractility with cardiomyofibers failing to maintain adequate mechanical tension. These mice develop progressive diastolic and systolic dysfunction, enlarged cardiac chambers, and die with congestive HF at ~1 year of age. Comprehensive survey of potential underlying mechanisms show that Sorbs2-cKO hearts have defective microtubule polymerization and compensatory upregulation of desmin, vinculin, and tubulins. Finally, consistent with our mouse observations, we identified suggestive links between Sorbs2 genetic variants and human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy. In conclusion, our studies show that Sorbs2 is essential for maintaining cytoskeletal structural integrity in CM, likely through strengthening the interactions between microtubules and other structural proteins at crosslink sites, and highlights its potential clinical relevance to cardiomyopathy.
Abstract P3089: Etv2 Functions As A Pioneer Transcription Factor To Regulate Endothelial Lineage Development And Reprogramming
Authors: Satyabrata Das, Javier Sierra-Pagan, Wuming Gong, Nikita Dsouza, Thijs Larson, Mary G Garry, Edgar Luzete-Monteiro, Kenneth S Zaret, Daniel J Garry
Journal: Circulation Research (2022)

The vasculature is an essential organ for the delivery of blood and oxygen to all tissues of the body and thus relevant to the treatment of ischemic heart disease. The ETS-related transcription factor 2 (ETV2) is a transcription factor that is both necessary and sufficient for the development of endothelial and blood lineages. However, the molecular mechanism by which ETV2 promotes endothelial and blood development is not known and warrants further investigation. Here, we report that ETV2 functions as a novel pioneer transcription factor that relaxes closed chromatin and regulates endothelial development. Pioneer factors are a subset of transcription factors that bind closed chromatin and promote chromatin relaxation in order to drive the development and reprogramming of cell lineages. By comparing embryonic stem cell differentiation and fibroblast reprogramming models with single cell RNA-seq, ATAC-seq, ChIP-seq and in-vitro nucleosomal binding techniques, we demonstrated that ETV2 was able to bind nucleosomal DNA and function as a pioneer factor independent of the cellular context. We also determined that ETV2 executed a pioneering role by recruiting and directly interacting with the ATP-dependent chromatin remodeling enzyme BRG1 to remodel chromatin around endothelial genes to help maintain an open configuration, resulting in increased H3K27ac deposition. Collectively, these results that define a novel pioneer factor and epigenetic regulatory pathways that govern the specification and differentiation of endothelial progenitor cells, will serve as a platform for targeted therapies to promote cardiovascular regeneration.
Abstract P2021: Blockade Or Deletion Of The Thromboxane/Prostanoid Receptor Reduces Right Ventricular Stiffness To Maintain Function In Right Ventricular Pressure Overload
Authors: James D West, Daniel Colvin, Christy Moore, Erica J Carrier
Journal: Circulation Research (2022)

The increased afterload of pulmonary arterial hypertension (PAH) impairs right ventricular function, as the RV struggles to adapt to increased pressure with remodeling and fibrosis. RV failure is the primary cause of death in PAH, and a frequent cause of death in pulmonary hypertension secondary to pulmonary embolism, emphysema, pulmonary fibrosis, and left-heart failure. There is currently no RV-specific therapeutic to maintain function and prolong patient life. During PAH, cardiomyocytes upregulate cell-surface expression of the G αq /IP 3 -coupled thromboxane/prostanoid receptor (TPr), which is activated by multiple endogenous ligands increased in PAH, and leads to calcium influx. TPr activation is also pro-fibrotic in multiple cell types and models. Previous studies have shown reduced fibrosis following TPr antagonism in mouse models of short-term pulmonary hypertension; however this effect has been variable in long-term studies. To more precisely determine the functional effects of TPr activation in RV pressure overload, we used pulmonary arterial banding (PAB) for a direct, sustained increase in pressure, antagonism or deletion of the TPr, and murine cardiac MRI for simultaneous evaluation of the RV and LV. TPr antagonism in a long-term PAB model improved RV ejection fraction and restored LV volume and output by preventing septal bulging and LV eccentricity. This occurred with even short-term antagonism, and was associated with decreased fibrosis in the septum and RV insertion points. Similar results were seen following PAB of universal or cardiomyocyte-specific TPr knockout mice; in all cases, decreasing TPr activation during RV pressure overload reduced RV stiffness even when RV fibrosis remained unchanged. In long-term pressure overload, the improved compliance with antagonism normalized expression of Yap/Taz-associated genes. These results suggest that TPr activation contributes to cardiomyocyte mechanotransduction and deleterious remodeling in response to the RV pressure overload of pulmonary hypertension, and that antagonism of the TPr may preserve RV function to prolong life in PAH patients.
Abstract P2030: Defining Transcription Factor Dependent Regulatory Networks In Cardiac Rhythm And Disease
Authors: Sonja Lazarevic, Zhezhen Wang, Kaitlyn Shen, Margaret Gadek, David Park, Ivan Moskowitz
Journal: Circulation Research (2022)

The transcriptional basis of homeostasis and disease is implied by the non-coding nature of genetic variation identified by GWAS. Functional genomic approaches to unveil the gene regulatory networks (GRNs) relevant to disease is therefore a high priority. Most models for transcriptional dysregulation presume that perturbation of a wild-type GRN causes disease risk. For example, the T-box transcription factor, TBX5, is essential for atrial rhythm homeostasis and directly drives a physiologically relevant GRN composed of cardiac channel genes. Alternatively, examination of the upregulated genes after the deletion of Tbx5 implicates the activation of a disease-specific GRN. Using TF-dependent noncoding RNA (ncRNA) profiling, through the differential deep ncRNA sequencing from atria of wild-type and Tbx5 mutant mice, we focused on the ncRNAs that were only active following the deletion of TBX5. Therefore, we identified putative TBX5-dependent enhancers, based on knowledge that ncRNAs can identify transcription at regulatory elements. We hypothesized that these regulatory elements may reveal disease-response enhancers, essential for coping with atrial dysfunction. We sought to identify the cell-specificity of these enhancers and therefore generated cell-type specific ATAC-seq datasets for left atrial tissue, cardiac fibroblasts, and cardiomyocytes, then overlapped each dataset with the ncRNAs. These candidate regulatory elements included a putative enhancer upstream of Sox9, a known modulator of cardiac fibrosis, along with other cardiac stress-response pathways, including mediators of TGF-β signaling. The ncRNA candidate is expressed in isolated cardiac fibroblasts treated with TGF-β, and the enhancer demonstrated luciferase activation in fibroblasts. To examine the hypothesis that the disease-acquired GRN in TBX5 mutant atria may be generalizable to other cardiac insults, we examined the transcriptional changes occurring in the left atria of a Transverse Aortic Constriction (TAC) mouse model. We revealed remarkable correlation between the differentially expressed genes between these disparate disease models. We also performed differential ncRNA profiling from this pressure overload mouse model, and identified the conservation of acquired ncRNAs when compared to the cardiac arrhythmia mouse model. The conservation of the transcriptional analysis and ncRNA candidates supports the paradigm of a common disease-specific GRN that mediates and may participate in the physiologic consequences of disease.
Abstract P2105: Precision Medicine In Pediatric Calmodulinopathy
Authors: K. Ashley Fetterman, Malorie Blancard, Mariam Jouni, Franck Potet, Gregory G Webster, Alfred L George, Paul W Burridge
Journal: Circulation Research (2022)

Calmodulinopathy is a life-threatening cardiac arrhythmia syndrome resulting from a single heterozygous mutation in any of the three calmodulin (CaM) genes. Most (68%) persons with a pathogenic CaM variant will experience a major arrhythmic event such as aborted cardiac arrest or sudden cardiac death by the age of five years. Calmodulinopathies result in heterogenous clinical features with one of the predominant clinical phenotypes being long QT syndrome (CaM-LQTS). Despite current treatments, 56% of calmodulinopathy patients experience breakthrough cardiac events, underscoring the need for improved therapeutics. A current barrier to effective treatment is our incomplete understanding of how calmodulin genetic variants contribute to pathological phenotypes. Human induced pluripotent stem cells (hiPSCs) can be differentiated into cardiomyocytes (hiPSC-CMs) while maintaining the patient’s genetic background. Application of hiPSC-CMs in the context of this disease allows us to better understand patient-specific heterogeneity at the cellular level. We have established a CaM-LQTS hiPSC-CM model using hiPSCs generated from five persons with a pathogenic CaM variant who present with CaM-LQTS. We hypothesize that we can model a CaM-LQTS phenotype using patient-specific hiPSC-CMs, identify clinically appropriate drugs that correct it, and determine underlying mechanisms that drive this phenotype. We have determined the cellular CaM-LQTS phenotype of each patient line using blinded electrophysiological, contractility, and calcium imaging studies and have identified FDA-approved drugs that alleviate these phenotypes. We are also performing experiments, with a focus on calcium cycling dysregulation, to identify underlying mechanisms that drive the cellular CaM-LQTS phenotype. In conclusion, these studies will provide a patient-specific methodology to identify necessary clinical treatments for CaM-LQTS and elucidate the drivers of this rare and severe disease.
Abstract P3119: Selectively Expressing Sars-Cov-2 Spike Protein S1 Subunit In Cardiomyocytes Induces Cardiac Hypertrophy In Mice
Authors: Caroline Sheldon, Steven Negron, Chase W Kessinger, Bing Xu, William T Pu, Chieh-Yu Lin, Zhiqiang Lin
Journal: Circulation Research (2022)

Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. By comparing the pathological effects of NL63-S and CoV-2 spike protein (CoV-2-S), we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses, which is independent of ACE2.We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine-rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated constructs that express membrane-localized CoV-2-S1 (S1-TM) or HCoV-NL63-S1 (NLS1-TM). AAV9-mediated, selective expression of the S1-TM and not NLS1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. In vitro, overexpressing S1-TM in cultured neonatal rat ventricular CMs induced hypertrophy, decreased Myh6 and increased IL-6 . In the ventricular biopsy of a deceased patient with COVID-19 associated myocarditis, Spike protein and TLR4 were detected in both CMs and non-CMs, and these two proteins were absent in a healthy pre-pandemic human heart. In the ventricular biopsy of a patient who died of modified RNA vaccine-associated myocarditis, the expression of Spike protein was only detected in a small fraction of CMs, and no obvious TLR4 signal was detected in CMs. Because CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S. Additionally, our data suggest that modified RNA vaccine unlikely causes myocarditis by directly transfecting the CMs.
Abstract P2011: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy
Authors: Chun Chou, Gregory Martin, Gayani Perera, Junya Awata, Robert M Blanton, Xuehong Cao, Abdullah Alissa, Christopher Madias, Jonas B Galper, Michael T Chin
Journal: Circulation Research (2022)

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, cardiac fibrosis and increased risk of sudden cardiac death, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset and complication. While mutations in the sarcomere gene can account for a substantial proportion of familial cases of HCM, up to 70% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of monozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased elastance, reduced end diastolic volume and increased E/E’ consistent with increased systolic and reduced diastolic function. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathological left ventricular hypertrophy with substantial cardiac fibrosis and progressively reduced ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Mice also were more susceptible to ventricular tachycardia with programmed stimulation. Single nuclei RNA-sequencing of mouse hearts is underway and preliminarily reveals reduction in oxidative phosphorylation, consistent with known effects of Cryab on mitochondrial function. Thus, our data establishes the Cryab R123W allele as a novel genetic model of HCM and unveiled additional sarcomere-independent mechanisms of cardiomyocyte hypertrophy.
Abstract P3117: Validating Genetic Risk Markers Causing Doxorubicin-induced Cardiotoxicity In African American And European American Pediatric Patients Using A Hipsc Model
Authors: Disheet A Shah, Yadav Sapkota, Paul W Burridge
Journal: Circulation Research (2022)

The W.H.O. estimates that globally 400,000 children under 19 are diagnosed with cancer annually. 60% of pediatric cancers are treated with chemotherapy using anthracyclines, mainly doxorubicin. Survivors of childhood cancer are approximately 15 times more likely to be diagnosed with congestive heart failure. African American (AA) survivors had a 2.5-fold increased risk of severe or life-threatening cardiomyopathy vs European Americans (EA). In recent WGS studies, 2 novel loci in chromosome 1 &amp; 6 were identified to be correlated with an increased risk of doxorubicin-induced cardiotoxicity (DIC) in AA and EA population groups respectively and were reduced or absent in the other group. Our study aims to validate these loci using patient specific hiPSC-derived cardiomyocytes (hiPSC-CM), and for that we recruited and generated 20 hiPSC lines from the blood of AA and EA pediatric patients. Using a novel bioreactor system, a large-scale production of hiPSC-CM for this patient specific samples is underway, and the cells will be utilized for phenotypic and genotypic characterization. Our aim is to assess the effect of doxorubicin on cardiomyocyte viability, apoptosis, mitochondrial function, and calcium dynamics. Differential cardiac gene regulation after exposure to doxorubicin will be studied using RNA sequencing. In conclusion, our findings will validate the genetic variants predisposing AA and EA populations to DIC. This study will clinically impact therapeutic approaches on both AA and EA populations and at individual levels while using doxorubicin. The validated hiPSC-CMs could help in identifying personalized cardioprotectants to reduce DIC without modifying chemotherapy. This study could also potentially provide data for genomically-informed drug discovery for novel cardioprotectants.
Carbamazepine and the lung
Authors: B Barreiro, F Manresa, J Valldeperas
Journal: European Respiratory Journal (1990)

A 69 yr old man was admitted with a 10 day history of fever, arthromyalgia, dyspnoea, dry cough and pleuritic pain. Temperature was 38 degrees C; tachypnoea 36 rpm. Extensive crackles were audible over both upper lung fields. Chest X-ray showed bilateral alveolar infiltrates. Forced vital capacity was 49% of predicted, and carbon monoxide transfer coefficient was 32% of predicted value. The patient had been taking carbamazepine for one month because of a trigeminal neuralgia. After withdrawal of the drug he gradually recovered.